Topical administration of basic antifungal compositions to treat fungal infections of the nails

ABSTRACT

Methods and topical pharmaceutical formulations are provided for the treatment of nail fungus (onychomycosis). The invention involves a pharmacologically active antifungal agent, plus a pharmaceutically acceptable base in a formulation having a pH of 7.5 to about 13.0, preferably about 8.0 to 11.5, and most preferably about 8.5 to 10.5. These basic formulations permeate the nail and are effective in treating fungal infections of the nail and surrounding tissues.

TECHNICAL FIELD

This invention relates generally to methods and pharmaceuticalformulations for treating fungal infections of the nail and adjacenttissue. More particularly, this invention relates to the use of apharmacologically active base in such methods and formulations.

BACKGROUND

Introduction

Fungal infections of the nail, referred to by the terms “nail fungus,”“onychomycosis,” or “tinea unguium,” are common throughout the world. Anestimated 2-13% of the population is affected in North America, with atleast 15-20% of those aged 40-60 having one or more fingernails ortoenails infected. Toenails are much more commonly affected thanfingernails. Infections can range from superficial, causing little morethan discoloration, to severe, resulting in loss of the nail togetherwith deformities of the surrounding digit. The incidence ofonychomycosis has been rising over the past few decades, due to factorssuch as an increased elderly population, increased participation invigorous physical activity while wearing moisture-retaining shoes andsocks, an increase in the number of HIV infected individuals, anincreased incidence of diabetes, and increased use of steroids,antibiotics, and other therapeutics that can suppress immunologicresponses to fungi.

While nail fungus is rarely life threatening, it causes significantpain, inconvenience, embarrassment, emotional distress, and limitationsto manual performance and ambulation. Individuals with moderate tosevere onychomycosis can lose their ability to perform many routinetasks (such as fastening buttons, picking up small objects, walkingsignificant distances) and can lose the ability to performsatisfactorily in their occupations. Due to the unpleasant appearance oftheir hands or feet, these individuals may become sociallyself-conscious and embarrassed, and may avoid intimate or other closecontact with people. Loss of self-esteem, anxiety, and depressioncommonly result from moderate to severe cases of fungal nail infection.

At present, topical treatments for nail fungus are rarely effective.Although some oral antifungal therapies have moderate efficacy, theyalso pose significant risks of toxic reactions, and many patients wouldprefer local, topical treatments to systemic treatments.

Etiology and Varieties

Onychomycosis is caused most commonly by several species ofdermatophytes (parasitic fungi that infect the keratin-rich tissue ofthe stratum corneum, hair, and nails) and, less commonly, bynondermatophyte molds or by yeasts, primarily of the genus Candida. Anestimated 90% of cases are caused by dermatophytes, primarily of thegenera Trichophyton, Microsporum, and Epidermophyton, while about 8% arecaused by nondermatophyte molds and 2% by yeasts. The causative agent inonychomycosis can rarely be determined by clinical appearance;microscopic examination or culturing is usually required. Furthermore,an infected nail colonized by one species can develop secondaryinfections by other fungi, yeasts, or bacteria.

Onychomycosis can affect the nail plate, the nail bed (the tissuedirectly under the nail plate), the nail matrix or nail root (thethickened skin at the base of the nail from which the nail platedevelops), the cuticle, the hyponychium (the thickened layer ofepidermis beneath the free end of the nail), and the proximal andlateral nail folds (the skin adjacent to the base and sides of thenail).

Factors that contribute to the development of onychomycosis includeadvanced age, diabetes (which reduces circulation to the extremities),wearing heat- and moisture-retaining footwear, communal bathing, HIVinfection, the use of antibiotics or immunosuppressive drugs, trauma tothe nail, use of insufficiently cleaned manicure tools, poor overallhealth, and warm climates.

Onychomycosis can be categorized into several varieties based onclinical appearance. The recognized varieties include:

Distal and lateral subungual onychomycosis (DLSO): This is the mostcommon variety. It usually results from a fungal infection of the skin(usually the plantar skin of the foot) spreading to the nail bed andthen to the underside of the nail plate via the hyponychium. The distaland lateral parts of the nail plate become thickened, white, and opaque.In addition, the nail bed becomes hyperkeratotic and onycholysis(separation of the nail plate from the bed, ultimately resulting in lossof the nail) commonly ensues. Paronychia (inflammation of the tissuesadjacent to the nail) is also common. Trichophyton rubrum is the mostcommon pathogen.

Endonyx onychomycosis (EO): This is a variety of DLSO in which thefungus spreads directly from the skin to the nail plate rather than tothe nail bed. The nail again is thickened, white, and opaque, but thereis no evident nail bed hyperkeratosis or onycholysis.

White superficial onychomycosis (WSO): This variety is almost alwaysfound on toenails. The surface of an infected nail develops white dotsor powdery patches and the nail becomes rough and crumbly. Trichophytonmentagrophytes (T. interdigitale) is the most common cause, though somenondermatophyte molds such as Acremonium, Aspergillus, and Fusarium canalso infect the upper surface of the nail plate. The nondermatophytemolds commonly cause black or green nails.

Proximal subungual onychomycosis (PSO): In this least common variety,the fungus first attacks the cuticle and proximal nail fold, and thenpenetrates the proximal nail plate. The distal part of the nail remainsnormal.

Candida Onychomycosis (CO): The yeast, nearly always Candida albicans,infects the nail folds (paronychia), the nail plate and surroundingtissues (in chronic mucocutaneous candidiasis), the nail bed, or anycombination of these. The entire digit commonly becomes swollen anddeformed. Candida may cause onycholysis or it may colonize onycholyticnails (resulting from trauma or another infection). Candida infectionassociated with paronychia is almost always secondary to trauma to thenail folds.

Total dystrophic onychomycosis (TDO): The entire nail plate isthickened, yellow-brown, and opaque. All the adjacent tissues areaffected, and the nail matrix may be permanently damaged, preventingnormal nail growth even after the infection resolves. TDO can be theendpoint of any of the other onychomycosis varieties.

A patient with onychomycosis may have one variety or any combination ofvarieties.

Current Treatments

Onychomycosis is presently treated primarily with oral antifungalagents. Topical agents are rarely effective by themselves, except inmild cases that only affect the distal nail plate. They may, however, bebeneficial in combination with oral therapy. In severe cases, theaffected nail (and sometimes the nail bed and matrix) is removedsurgically or by use of a urea containing formulation; removal of thenail is done in conjunction with oral and sometimes topical therapy.Further details on some of these methods follow.

Oral medications: The preferred therapy for onychomycosis is orallyadministered treatment with terbinafine (Lamisil™), itraconazole(Sporanox™), or fluconazole (Diflucan™). Terbinafine, an allylamine, isactive against dermatophytes, but has considerably less efficacy againstnondermatophyte molds and against yeasts. Itraconazole and fluconazoleare triazoles that are effective against dermatophytes, nondermatophytemolds, and yeasts. When administered daily, all of these compounds cancause hepatic injury, and monitoring of liver enzymes is required. Pulsetherapy (typically, administration one week per month) reduces the risksfor hepatic damage, but prolongs the course of therapy from about 6 to12 weeks to at least several months. Terbinafine has several potentiallyserious drug interactions, and the triazoles, because they aremetabolized using the hepatic cytochrome P450 system, have numeroussignificant drug and food interactions that prevent their use in manypatients. Even though these drugs are the currently preferred treatmentsfor onychomycosis, their cure rates are not high: a recent survey (ArchDermatol 134(12):1551-1554, 1998) found that standard treatment withterbinafine resulted in disease-free nails in approximately 35-50% ofcases, while the rate for itraconazole was approximately 25-40%. Relapseis also common, though precise figures are not available. These oraltherapies are nevertheless more effective than topical treatmentsbecause they apparently penetrate the nail more quickly and thoroughly,and because they remain in the nail for weeks or months followingtreatment.

Topical treatments: Topical antifungal treatments are now administeredmainly in cases where the fungal infection is restricted to the distalhalf of the nail plate or in cases in which the patient cannot tolerateoral therapy. Again, their low efficacies appear due mainly to theirinability to adequately penetrate the nail. Topical antifungal agentsinclude allylamines (including terbinafine), triazoles (includingitraconazole and fluconazole), imidazole derivatives (includingketoconazole, miconazole, clotrimazole, and enconazole), amorolfine,ciclopirox olamine, sodium pyrithione, bifonazole plus urea, andpropylene glycol plus urea plus lactic acid.

Existing treatments for onychomycosis are thus of limited efficacy, havehigh risks for adverse effects and drug interactions, and are timeconsuming and inconvenient for the patient. Furthermore, (based onconversations with practicing dermatologists) a large majority ofonychomycosis patients would prefer a local, topical treatment to asystemic treatment that carries a significant risk of adverse effects.It has now been discovered that certain basic compositions, when used asdescribed herein to enhance the permeation of antifungal compounds intothe nail and surrounding tissues, successfully treat nail funguslocally, with much higher efficacy than for other topical treatments.The present invention provides a novel treatment for nail fungus that iseffective, safe, not painful, and convenient.

SUMMARY OF THE INVENTION

It is accordingly a primary object of the invention to address the aboveneeds in the art by providing a novel method and formulation for thetreatment of fungal infections of the nail and surrounding tissues(onychomycosis).

The invention provides a method and formulation for the treatment ofonychomycosis that involves a topically applied formulation containing apharmacologically active base in an amount effective to provide theformulation with a pH in the range of about 7.5 to 13.0, preferablyabout 8.0 to 11.5, and most preferably about 8.5 to 10.5. The baseitself has antifungal activity, but additional antifungal agents may beincorporated into the formulation as well, in which case the base notonly provides antifungal activity but also enhances the permeation ofthe additional antifungal agent(s) into and through the skin. Theformulation may be a lotion, cream, solution, paste, ointment, plaster,paint, bioadhesive, or the like, or may be contained in a tape or in askin patch comprised of a laminated composite intended for long-termadhesion to the body surface (typically throughout a delivery period inthe range of about 8 to about 72 hours) in the affected area.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and Nomenclature

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specificpharmacologically active bases, antifungal agents, carriers, formulationtypes, treatment regimens, and so forth, as such may vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise.

The term “onychomycosis” is used herein to refer to any fungal infectionof the fingernail or toenail; such infection commonly encompasses someor all of the surrounding tissues. Surrounding tissues comprise the nailbed, the nail matrix, the nail root, the nail folds, the cuticle, andthe hyponychium. Infection may be by dermatophytes, nondermatophytemolds, yeasts, other fungi, or combinations of these. Infectingdermatophytes include, without limitation, members of the generaTrichophyton (including T. rubrum, T. interdigitale (T. mentagrophytes),and T. soudanense), Epidermophyton, and Microsporum. Infectingnondermatophyte molds include, without limitation, members of the generaAcremonium, Aspergillus, Fusarium, Onychocola, and Scytalidium.Infecting yeasts include, without limitation, members of the genusCandida, including Candida albicans. The terms “onychomycosis”, “tineaunguium”, “nail fungus”, and “fungal infection of the nail” all haveessentially the identical meaning and are used interchangeably herein.

The term “pharmacologically active base” is used herein to refer to abasic compound or composition of matter that is an effective antifungalagent and that, when included in a topical pharmaceutical formulationthat contains one or more additional pharmacologically active antifungalagents, enhances permeation of the formulation and the additionalantifungal agent(s) into the nail or skin of a human patient. The term“enhances permeation” is used herein to refer to an increase inpermeation by the pharmacologically active antifungal agent into thenail or skin of at least 20%, preferably at least 50%, and morepreferably at least 100%.

The terms “pharmacologically active antifungal agent” and “antifungalagent” are used herein interchangeably to refer to a pharmaceuticallyacceptable agent that, when topically administered to a human patienttogether with a pharmacologically active base of the invention, inducesa desired pharmacologic and/or physiologic effect by local and/orsystemic action, i.e., prevention or treatment of onychomycosis. Alsoincluded are derivatives and analogs of those compounds or classes ofcompounds specifically mentioned that also induce the desired effect.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptablederivative,” is meant a compound that is not biologically or otherwiseundesirable, i.e., the compound may be incorporated into a topicalformulation of the invention and administered to a patient withoutcausing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the formulationin which it is contained. A “pharmacologically active” compound refersto an active agent as defined above, or to an analog or derivativethereof having the same type of pharmacological activity as the parentcompound.

The terms “treating” and “treatment” as used herein refer to actionsthat reduce the severity and/or frequency of symptoms, eliminatesymptoms and/or their underlying cause, prevent the occurrence ofsymptoms and/or their underlying cause, and improve or remediate damage.The present method of “treating” a patient, as the term is used herein,thus encompasses both prevention of onychomycosis in a predisposedindividual and treatment of onychomycosis in a clinically symptomaticindividual.

The term “base” is used in its traditional sense, i.e., a substance thatdissolves in water to produce hydroxide ions. The water is typically anaqueous fluid, and may be natural moisture at the skin surface, or thepatch or composition that is used may contain added water, and/or beused in connection with an occlusive backing. Similarly, any liquid orsemisolid formulation that is used is preferably aqueous or used inconjunction with an overlayer of an occlusive material. Any base may beused provided that the compound provides free hydroxide ions in thepresence of an aqueous fluid. Bases can provide free hydroxide ionseither directly or indirectly and thus can also be referred to as“hydroxide-releasing agents”. Hydroxide-releasing agents that providefree hydroxide ions directly, typically contain hydroxide groups andrelease the hydroxide ions directly into solution, for example, alkalimetal hydroxides. Hydroxide-releasing agents that provide free hydroxideions indirectly, are typically those compounds that are acted uponchemically in an aqueous environment and the reaction produces hydroxideions, for example metal carbonates or amines.

By an “effective” amount or a “therapeutically effective amount” of apharmacologically active agent is meant a nontoxic but sufficient amountof the drug or agent to provide the desired effect, i.e., prevention ortreatment of onychomycosis. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, mode of administration, and the like. Thus, it is notalways possible to specify an exact “effective amount.” However, anappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The term “topical administration” is used in its conventional sense tomean delivery of a topical drug or pharmacologically active agent to theskin, nail, or mucosal tissue, as in, for example, the treatment ofonychomycosis.

The term “body surface” is used to refer to skin, nail, or mucosaltissue.

“Carriers” or “vehicles” as used herein refer to pharmaceuticallyacceptable carrier materials suitable for topical drug administration.Carriers and vehicles useful herein include any such materials known inthe art that are nontoxic and do not interact with other components ofthe composition in a deleterious manner.

The term “aqueous” refers to a formulation that contains water or thatbecomes water-containing following application to the skin, nail, ormucosal tissue.

In describing molecular structures and formulae herein, the phrase“having the formula” or “having the structure” is not intended to belimiting and is used in the same way that the term “comprising” iscommonly used.

The term “alkyl” as used herein refers to a branched or unbranchedsaturated hydrocarbon group typically although not necessarilycontaining 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, aswell as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like.Generally, although again not necessarily, alkyl groups herein contain 1to about 12 carbon atoms. The term “lower alkyl” denotes an alkyl groupof one to six carbon atoms, preferably one to four carbon atoms.“Substituted alkyl” refers to alkyl substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkyl” and“heteroalkyl” refer to alkyl in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkyl” and “lower alkyl” include linear, branched, cyclic,unsubstituted, substituted, and/or heteroatom-containing alkyl or loweralkyl.

The term “alkenyl” as used herein refers to a branched or unbranchedhydrocarbon group typically although not necessarily containing 2 toabout 24 carbon atoms and at least one double bond, such as ethenyl,n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, andthe like. Generally, although again not necessarily, alkenyl groupsherein contain 2 to about 12 carbon atoms. The term “lower alkenyl”denotes an alkenyl group of two to six carbon atoms, preferably two tofour carbon atoms. “Substituted alkenyl” refers to alkenyl substitutedwith one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl inwhich at least one carbon atom is replaced with a heteroatom.

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, linked covalently, or linked toa common group such as a methylene or ethylene moiety. The commonlinking group may also be a carbonyl as in benzophenone, an oxygen atomas in diphenylether, or a nitrogen atom as in diphenylamine. Preferredaryl groups contain one aromatic ring and are referred to as “monocyclicaryls.” “Substituted aryl” refers to an aryl moiety substituted with oneor more substituent groups, and the terms “heteroatom-containing aryl”and “heteroaryl” refer to aryl in which at least one carbon atom isreplaced with a heteroatom.

The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a molecule or molecular fragment in whichone or more carbon atoms are replaced with an atom other than carbon,e.g., nitrogen, oxygen, sulfur, phosphorus, or silicon. Similarly, theterm “heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the term “heteroaryl” refersto an aryl substituent that is heteroatom-containing, and the like. Whenthe term “heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. That is, the phrase “heteroatom-containingalkyl, alkenyl, and alkynyl” is to be interpreted as“heteroatom-containing alkyl, heteroatom-containing alkenyl, andheteroatom-containing alkynyl.”

By “substituted”, as in “substituted alkyl,” “substituted alkenyl,”“substituted aryl,” and the like, as alluded to in some of theaforementioned definitions, is meant that in the alkyl, alkenyl, aryl,or other moiety, at least one hydrogen atom bound to a carbon atom isreplaced with one or more substituents that are functional groups suchas hydroxyl, alkoxy, thio, amino, halo, and the like.

The terms “alkyl,” “alkenyl,” “aryl,” and the like are, unless otherwiseindicated, intended to include unsubstituted, substituted,heteroatom-containing, and substituted heteroatom-containingsubstituents.

II. Indications

The invention pertains to treatment of an individual predisposed to orafflicted with onychomycosis, comprising topically administering apharmaceutical formulation containing a base to the affected skin area,wherein the formulation preferably has a pH in the range of about 7.5 toabout 13.0, preferably about 8.0 to 11.5, more preferably about 8.5 to11.5, and most preferably about 8.5 to 10.5. In some aspects, the pHwill be in the range of about 9.5 to 11.5, preferably 10.0 to about11.5. The formulation will generally include a pharmacologically activeantifungal agent as well, in which case the base serves as a permeationenhancer for the agent. Inclusion of the antifungal agent is optional,however, insofar as the base does exhibit some antifungal activity. Theterm “onychomycosis” comprises any fungal infection of the fingernail ortoenail and surrounding tissues, including infection by dermatophytes,nondermatophyte molds, and yeasts.

III. The Pharmacologically Active Base

The pharmacologically active base of the invention is an inorganic or anorganic pharmaceutically acceptable base. Preferred inorganic basesinclude inorganic hydroxides, inorganic oxides, inorganic salts of weakacids, and combinations thereof. Preferred organic bases are nitrogenousbases.

It has long been thought that strong bases, such as NaOH, were notsuitable for administration to skin because they would damage skin. Ithas been now been discovered that the skin permeability of various drugscould be enhanced without skin damage by exposing the skin to a base orbasic solution, in a skin contacting formulation or patch. The desiredpH of the solution on the skin can be obtained using a variety of basesor base concentrations. Accordingly, the pH is selected so as to be lowenough so as to not cause skin damage, but high enough to enhance skinpermeation to various active agents. As such, it is important that theamount of base in any patch or formulation is optimized so as toincrease the flux of the drug through the body surface while minimizingany possibility of skin damage. In general, this means that the pH atthe body surface in contact with a formulation or drug delivery systemof the invention is preferably in the range of approximately 8.0 to13.0, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5and most preferably about 8.5 to 10.5. In some aspects, the pH will bein the range of about 9.5 to 11.5, preferably 10.0 to about 11.5.

In one preferred embodiment, the pH at the body surface is the primarydesign consideration, i.e., the composition or system is designed so asto provide the desired pH at the body surface. Anhydrous formulationsand transdermal systems may not have a measurable pH, and theformulation or system can be designed so as to provide a target pH atthe body surface. Moisture from the body surface can migrate into theformulation or system, dissolve the base and thus release the base intosolution, which will then provide the desired target pH at the skin'ssurface. In those instances, a hydrophilic composition is preferred. Inaddition, when using aqueous formulations, the pH of the formulation maychange over time after it is applied on the skin. For example, gels,solutions, ointments, etc., may experience a net loss of moisture afterbeing applied to the body surface, i.e., the amount of water lost isgreater than the amount of water received from the body surface. In thatcase, the pH of the formulation may be different than its pH whenmanufactured. This problem can be easily remedied by designing theaqueous formulations to provide a target pH at the skin's surface.

In other embodiments of the invention, the pH of the formulation or thedrug composition contained within a delivery system will be in the rangeof approximately 8.0 to 13.0, preferably about 8.0 to 11.5, mostpreferably about 8.5 to 11.5, and most preferably about 8.5 to 10.5. Insome aspects, the pH will be in the range of about 9.5 to 11.5,preferably 10.0 to 11.5. In one embodiment of the invention the pH ofthe formulation is higher than the pH at the body surface. For example,if an aqueous formulation is used, moisture from the body surface candilute the formulation, and thus provide for a different pH at the bodysurface, which will typically be lower than that of the formulationitself.

In one preferred embodiment, the body surface is exposed to a base orbasic solution for a sufficient period of time so as to provide a highpH at the body surface, thus creating channels in the skin or mucosa forthe drug to go through. It is expected that drug flux is proportional tothe strength of the solution and the duration of exposure. However, itis desirable to balance the maximization of drug flux with theminimization of skin damage. This can be done in numerous ways. Forexample, the skin damage may be minimized by selecting a lower pH withinthe 8.0 to 13.0 range, by exposing the skin to the formulation or systemfor a shorter period of time, or by including at least oneirritation-mitigating additive. Alternatively, the patient can beadvised to change the location of application with each subsequentadministration.

While certain preferred amounts are set forth below, it is understoodthat, for all of the inorganic and organic bases described herein, theoptimum amount of any such base will depend on the strength or weaknessof the base and its molecular weight, and other factors such as thenumber of ionizable sites in the active agent being administered andwhether there are any acidic species present in the formulation orpatch. One skilled in the art may readily determine the optimum amountfor any particular base such that the degree of enhancement is optimizedwhile the possibility of damage to the body surface is eliminated or atleast substantially minimized.

Inorganic Base

Exemplary inorganic bases are inorganic hydroxides, inorganic oxides,inorganic salts of weak acids, and combinations thereof. Preferredinorganic bases are those whose aqueous solutions have a high pH, andare acceptable as food or pharmaceutical additives. Examples of suchpreferred inorganic bases are those listed below, along with theirrespective pHs. Some of the bases are identified by their hydrate forms,and it is understood that when referring to a “base”, both the hydratedand non-hydrated forms are intended to be included.

Inorganic base pH of Aqueous Solution (concentration) Ammoniumhydroxide^(1,2,3) 11.27 (1 N), 10.27 (0.001 N) Sodium hydroxide^(1,2,3)14(5%), 13 (0.5%), 12 (0.05%) Potassium hydroxide^(1,2,3) 13.5 (0.1 M)Calcium hydroxide^(1,3) 12.4 (saturated solution in water) Magnesiumhydroxide^(1,3) 9.5 to 10.5 slurry Magnesium oxide^(1,2,3) 10.3(saturated aqueous solution) Calcium oxide³ Soluble in water, FormCa(OH)₂ Sodium acetate^(1,3) ˜8.9 (0.1 N) Sodium acetate,trihydrate^(1,2) 8.9 (0.1 N) Sodium acetate, anhydrous^(1,2) ˜8.9 (0.1N) Sodium borate decahydrate^(1,2) ˜8.8-9.4, 9.15 to 9.2 (0.01 M) Sodiumborate^(1,2,3) 8.8-9.4, 9.15 to 9.2 (0.01 M) Sodium metaborate Stronglyalkaline Sodium carbonate^(1,2,3) ˜11.6 Sodium carbonate hydrate¹ ˜11.6Sodium carbonate anhydrous ˜11.6 Sodium bicarbonate^(1,2,3) 8.3 (0.1 Mfresh) Sodium phosphate, tribasic^(1,3) ˜11.5 (0.1%), ˜11.7 (0.5%),˜11.9 (1.0%) Sodium phosphate, tribasic 11.5 (0.1%), 11.7 (0.5%), 11.9(1.0%) dodecahydrate Sodium phosphate, dibasic, 9.1 (1%) anhydrous^(1,2)Sodium phosphate, dibasic, ˜9.5 heptahydrate^(1,2) Sodium phosphate,dibasic^(1,3) ˜9.5 Sodium phosphate, dibasic, ˜9.5 dihydrate¹ Sodiumphosphate, dibasic, ˜9.5 dodecahydrate Potassium carbonate^(1,3) ˜11.6Potassium bicarbonate³ 8.2 (0.1 M) Potassium citrate^(1,2,3) ˜8.5Potassium citrate ˜8.5 monohydrate Potassium acetate^(1,3) 9.7 (0.1 M)Potassium phosphate, Aqueous solution is slightly alkaline dibasic^(1,2)Potassium phosphate, tribasic³ Aqueous solution is strongly alkalineAmmonium phosphate, ˜8 dibasic^(1,2,3) ¹listed in the “Chemicals inCompliance with Pharmaceutical Standards: Inactive Ingredient Guide”²listed in the “Handbook of Pharmaceutical Additives” ³listed in theFDA's food additive database

Inorganic Hydroxides

Inorganic hydroxides include, for example, ammonium hydroxide, alkalimetal hydroxide and alkaline earth metal hydroxides, and mixturesthereof. Preferred inorganic hydroxides include ammonium hydroxide;monovalent alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; divalent alkali earth metal hydroxides such ascalcium hydroxide and magnesium hydroxide; and combinations thereof.

The amount of inorganic hydroxide included in the compositions andsystems of the invention, will typically represent about 0.3-7.0 wt %,preferably 0.5-4.0 wt %, more preferably about 0.5-3.0 wt %, mostpreferably about 0.75-2.0 wt %, of a topically applied formulation or ofa drug reservoir of a drug delivery system, or patch.

The aforementioned amounts are particularly applicable to thoseformulations and patches in which the active agent is (1) an unchargedmolecule, e.g., wherein a basic drug is in nonionized, free-base form,(2) a basic salt of an acidic drug, or (3) there are no additionalspecies in the formulation or patch that could react with or beneutralized by the inorganic hydroxide, to any significant degree.

For formulations and patches in which the drug is in the form of an acidaddition salt, and/or wherein there are additional species in theformulations or systems that can be neutralized by or react with theinorganic base (i.e., acidic inactive ingredients), the amount ofinorganic hydroxide is preferably the total of (1) the amount necessaryto neutralize the acid addition salt and/or other base-neutralizablespecies (i.e., the “acidic species”), plus (2) about 0.3-7.0 wt %,preferably 0.5-4.0 wt %, more preferably about 0.5-3.0 wt %, mostpreferably about 0.75-2.0 wt %, of the formulation or drug reservoir.That is, for an acid addition salt, the enhancer is preferably presentin an amount just sufficient to neutralize the salt, plus an additionalamount (i.e., about 0.3-7.0 wt %, preferably 0.5-4.0 wt %, morepreferably about 0.5-3.0 wt %, most preferably about 0.75-2.0 wt %) toenhance the flux of the drug through the skin or mucosal tissue. Basicdrugs in the form of a neutral, free base or basic salt of acidic drugare usually not affected by a base, and thus for these drugs, the amountin (1) is usually the amount necessary to neutralize inactive componentsthat are acidic. For patches, the aforementioned percentages are givenrelative to the total weight of the formulation components and theadhesive, gel or liquid reservoir.

Still greater amounts of inorganic hydroxide may be used by controllingthe rate and/or quantity of release of the base, preferably during thedrug delivery period itself.

Inorganic Oxides

Inorganic oxides include, for example, magnesium oxide, calcium oxide,and the like.

The amount of inorganic oxide included in the compositions and systemsof the invention may be substantially higher than the numbers set forthabove for the inorganic hydroxide, and may be as high as 20 wt %, insome cases as high as 25 wt % or higher, but will generally be in therange of about 2-20 wt %. These amounts may be adjusted to take intoconsideration the presence of any base-neutralizable species.

Inorganic Salts of Weak Acids

Inorganic salts of weak acids include, ammonium phosphate (dibasic);alkali metal salts of weak acids such as sodium acetate, sodium borate,sodium metaborate, sodium carbonate, sodium bicarbonate, sodiumphosphate (tribasic), sodium phosphate (dibasic), potassium carbonate,potassium bicarbonate, potassium citrate, potassium acetate, potassiumphosphate (dibasic), potassium phosphate (tribasic); alkaline earthmetal salts of weak acids such as magnesium phosphate and calciumphosphate; and the like, and combinations thereof.

Preferred inorganic salts of weak acids include, ammonium phosphate(dibasic) and alkali metal salts of weak acids.

The amount of inorganic salts of weak acids included in the compositionsand systems of the invention may be substantially higher than thenumbers set forth above for the inorganic hydroxide, and may be as highas 20 wt %, in some cases as high as 25 wt % or higher, but willgenerally be in the range of approximately 2-20 wt %. These amounts maybe adjusted to take into consideration the presence of anybase-neutralizable species.

Organic Bases

Organic bases suitable for use in the invention are compounds having anamino group, amido group, an oxime, a cyano group, an aromatic ornon-aromatic nitrogen-containing heterocycle, a urea group, andcombinations thereof. More specifically, examples of suitable organicbases are nitrogenous bases, which include, but are not limited to,primary amines, secondary amines, tertiary amines, amides, oximes, cyano(—CN) containing groups, aromatic and non-aromatic nitrogen-containingheterocycles, urea, and mixtures thereof. Preferred organic bases areprimary amines, secondary amines, tertiary amines, aromatic andnon-aromatic nitrogen-containing heterocycles, and mixtures thereof.

For nitrogenous bases, the amount of the agent will typically representabout 0.5-4.0 wt %, preferably about 0.5-3.0 wt %, more preferably about0.75-2.0 wt %, of a topically applied formulation or of a drug reservoirof a drug delivery system or a patch. These amounts may be adjusted totake into consideration the presence of any base-neutralizable species.

Still greater amounts of the nitrogenous base may be used depending onthe strength of the base and the rate and/or quantity of release of thenitrogenous base preferably during the drug delivery period itself.

Preferred organic bases are those whose aqueous solutions have a high pHor a high pKa (more preferably a pKa>9), and are acceptable as food orpharmaceutical additives. Examples of such preferred organic bases arethose listed below, along with their respective pHs (or pKa values).

pH of Aqueous Organic base Solution (concentration)2-amino-2-methyl-1,3-propanediol¹ 10.8 (0.1 m)2-amino-2-methyl-1-propanol¹ 11.3 (0.1 m) Diethanolamine¹ 11.0 (0.1 N)Triethanolamine¹ 10.5 (0.1 N) Butylamine² pKa = 10.56 Dimethylamine²Strong base, pKa = 10.73 Cyclohexylamine² Strong base, pKa = 10.64Ethylenediamine² Strong base, pKa = 10.71 Isopentylamine² pKa = 10.6Monoethanolamine² 12.1 (25%), 12.05 (0.1 N), pKa = 9.4 Phenethylamine²Strong base, pKa = 9.83 Piperidine² Strong base, pKa = 11.12Pyrrolidine² Strong base, pKa = 11.27 Trimethylamine² Strong base, pKa =9.81 ¹listed in the “Handbook of Pharmaceutical Additives” ²listed inthe FDA's food additive database

Amines

Suitable nitrogenous bases may contain any one or a combination of thefollowing:

primary amino (—NH₂) groups;

mono-substituted (secondary) amino groups —NHR where R is hydrocarbyl,generally either alkyl or aryl, e.g., lower alkyl or phenyl, and may besubstituted with one or more nonhydrocarbyl substituents, e.g., 1 to 3halo, hydroxyl, thiol, or lower alkoxy groups (such —NHR groups include,for example, methylamino, ethylamino, isopropylamino, butylamino,cyclopropylamino, cyclohexylamino, n-hexylamino, phenylamino,benzylamino, chloroethylamino, hydroxyethylamino, etc.);

di-substituted (tertiary) amino groups —NR^(a)R^(b) where R^(a) andR^(b) may be the same or different and are as defined above for R(suitable —NR^(a)R^(b) include, for example, dimethylamino,diethylamino, diisopropylamino, dibutylamino, methylpropylamino,methylhexylamino, methylcyclohexylamino, ethylcyclopropylamino,ethylchloroethylamino, methylbenzylamino, methylphenylamino,methyltoluylamino, methyl-p-chlorophenylamino, methylcyclohexylamino,etc.);

amides —(CO)—NR^(c)R^(d) where R^(c) and R^(d) may be the same ordifferent and are either hydrogen or R, wherein R is as defined above(including, for example, amides wherein one of R^(c) and R^(d) is H andthe other is methyl, butyl, benzyl, etc.);

cyano (—CN);

aromatic nitrogen-containing heterocycles, typically five- orsix-membered monocyclic substituents, or bicyclic fused or linked five-or six-membered rings (such as pyrrolyl, pyrrolidinyl, pyridinyl,quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl,tetrazolyl, etc.); and

non-aromatic nitrogen-containing heterocycles, typically four- tosix-membered rings, including lactams and imides, e.g., pyrrolidino,morpholino, piperazino, piperidino, N-phenyl—propiolactam,-butyrolactam, -caprolactam, acetimide, phthalimide, succinimide, etc.

Primary amines, secondary amines, and tertiary amines may be genericallygrouped as encompassed by the molecular structure NR¹R²R³ wherein R¹, R²and R³ are selected from H, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,hydroxyalkenyl, alkoxyalkenyl, cycloalkyl, cycloalkyl-substituted alkyl,monocyclic aryl, and monocyclic aryl-substituted alkyl, with the provisothat at least one of R¹, R² and R³ is other than H. Examples of suchamines include, without limitation, diethanolamine, triethanolamine,isopropanolamine, triisopropanolamine, dibutanol amine, tributanolamine, N-dodecylethanolamine, N-(2-methoxyethyl) dodecylamine,N-(2,2-dimethoxyethyl)dodecylamine, N-ethyl-N-(dodecyl)ethanolamine,N-ethyl-N-(2-methoxyethyl)dodecylamine, N-ethyl-N-(2,2-dimethoxyethyl)dodecylamine, dimethyldodecylamine-N-oxide, monolauroyl lysine,dipalmitoyl lysine, dodecylamine, stearylamine, phenylethylamine,triethylamine, PEG-2 oleamine, PEG-5 oleamine, dodecyl2-(N,N-dimethylamino)propionate, bis(2-hydroxyethyl)oleylamine, andcombinations thereof.

Exemplary primary amines include 2-aminoethanol, 2-aminoheptane,2-amino-2-methyl-1,3 propanediol, 2-amino-2-methyl-1-propanol,n-amylamine, benzylamine, 1,4-butanediamine, n-butylamine,cyclohexylamine, ethylamine, ethylenediamine, methylamine,α-methylbenzylamine, phenethylamine, propylamine, andtris(hydroxymethyl)aminomethane.

Exemplary secondary amines include compounds that contain groups such asmethylamino, ethylamino, isopropylamino, butylamino, cyclopropylamino,cyclohexylamino, n-hexylamino, phenylamino, benzylamino,chloroethylamino, hydroxyethylamino, and so forth. Exemplary secondaryamines include diethanolamine, diethylamine, diisopropylamine, anddimethylamine.

Exemplary tertiary amines include compounds that contain groups such asdibutylamino, diethylamino, dimethylamino, diisopropylamino,ethylchloroethylamino, ethylcyclopropylamino, methylhexylamino,methylcyclohexylamino, methylpropylamino, methylbenzylamino,methyl-p-chlorophenylamino, methylcyclohexylamino, methylphenylamino,methyltoluylamino, and so forth. Exemplary tertiary amines includeN,N-diethylaniline, N,N-dimethylglycine, triethanolamine, triethylamine,and trimethylamine.

Amides

Amides, as will be appreciated by those skilled in the art, have themolecular structure R⁴—(CO)—NR⁵R⁶ where R⁴, R⁵ and R⁶ are generallyselected from H, alkyl, cycloalkyl, cycloalkyl-substituted alkyl,monocyclic aryl, and monocyclic aryl-substituted alkyl. Examples ofsuitable amides herein include, without limitation,hexamethyleneacetamide, hexamethyleneoctamide, hexamethylene lauramide,hexamethylene palmitamide, N,N-dimethyl formamide, N,N-dimethylacetamide, N,N-dimethyloctamide, N,N-dimethyldecamide, toluamide,dimethyl-m-toluamide, diethyl-m-toluamide, and combinations thereof.

Nitrogen-containing Heterocycles

Nitrogen-containing heterocycles suitable as the pharmacologicallyactive base herein include, by way of example, 2-pyrrolidone,1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,1-propyl-3-dodecylpyrrolidine, 1-dodecyclazacycloheptan-2-one, ethylenethiourea, hydantoin, oxalylurea, imidazolidilyl urea, N-octadecylmorpholine, dodecylpyridinium, N-dodecylpyrrolidine,N-dodecylpiperidine, N-dodecylhomopiperidine, and combinations thereof.

Aromatic nitrogen-containing heterocycles, typically contain a 5- or6-membered monocyclic substituent, or a bicyclic fused or linked 5- or6-membered ring, such as imidazolyl, indolyl, pyridinyl, pyrimidinyl,pyrrolyl, quinolinyl, tetrazolyl, 1,2,4-triazolyl, etc.

Aromatic nitrogen-containing heterocycles suitable as the organic baseherein include, by way of example, 2-amino-pyridine, benzimidazole,2,5-diaminopyridine, 2,4-dimethylimidazole, 2,3-dimethylpyridine,2,4-dimethylpyridine, 3,5-dimethylpyridine, imidazole, methoxypyridine,γ-picoline, 2,4,6-trimethylpyridine, and combinations thereof.

Non-aromatic nitrogen-containing heterocycles, typically contain 4- to6-membered rings such as acetimido, morpholinyl, lactams and imides(e.g., -butyrolactam, -caprolactam, N-phenyl—propiolactam), phthalimido,piperidyl, piperidino, piperazinyl, pyrrolidinyl, succinimido, etc.

Non-aromatic nitrogen-containing heterocycles include, by way ofexample, 1,2-dimethylpiperidine, 2,5-dimethylpiperazine,1,2-dimethylpyrrolidine, 1-ethylpiperidine, n-methylpyrrolidine,morpholine, piperazine, piperidine, pyrrolidine,2,2,6,6-tetramethylpiperidine, 2,2,4-trimethylpiperidine, andcombinations thereof.

For all pharmacologically active bases herein, the optimum amount of anyparticular agent will depend on the strength or weakness of the base,the molecular weight of the base, and other factors such as the numberof ionizable sites in the drug administered and any other acidic speciesin the formulation or patch. One skilled in the art may readilydetermine the optimum amount for any particular agent by ensuring that aformulation is effective to provide a pH at the skin surface, uponapplication of the formulation, in the range of about 7.5 to about 13.0,preferably about 8.0 to about 11.5, and most preferably in the range ofabout 8.5 to about 10.5. This in turn ensures that the degree oftreatment is maximized while the possibility of damage to the bodysurface is eliminated or at least substantially minimized.

IV. Pharmaceutical Formulations and Skin Patches

The pharmaceutical formulation of the invention comprises apharmaceutically acceptable topical carrier, a base (which serves as anantifungal agent), and, preferably, an additional pharmacologicallyactive antifungal compound (in which case the base also serves as apermeation enhancer for the compound). The base is present at aconcentration sufficient to provide a formulation pH in the range ofapproximately 7.5 to 13.0, preferably about 8.0 to 11.5, and mostpreferably about 8.5 to 10.5.

Pharmacologically active antifungal agents include, without limitation:amorolfine; ciclopirox olamine; flucytosine; griseofulvin; haloprogrin;potassium iodide sodium pyrithione; undecylenic acid; imidazolederivatives, including without limitation bifonazole, butoconazole,clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, andsulconazole; triazoles, including without limitation itraconazole,fluconazole, and terconazole; allylamines, including without limitationnaftifine and terbinafine; polyene antifungal antibiotics such asamphotericin B and nystatin; antifungal organic acids such as benzoicacid, salicylic acid, propionic acid, and caprylic acid; and a propyleneglycol-urea-lactic acid combination. One or more additional activeantifungal agents may optionally be present in the formulation. Thechoice of a particular pharmacologically active fungal agent will bereadily apparent to those skilled in the art. For example, anonychomycotic infection caused by a dermatophyte may be treated by anantifungal agent effective against dermatophytes, such as terbinafine.As another example, a case of onychomycosis of uncertain fungal etiologymay be treated with a broad-spectrum antifungal agent effective againstdermatophytes, nondermatophyte molds, and yeasts, such as itraconazole.Preferred antifungal agents include amorolfine, ciclopirox olamine,terbinafine, itraconazole, fluconazole, clotrimazole, and nystatin.

The formulation may be in any form suitable for application to the nailand surrounding tissues, and may comprise, for example, a cream, lotion,solution, gel, ointment, paste, plaster, paint, bioadhesive, or thelike, and/or may be prepared so as to contain liposomes, micelles,and/or microspheres. For those formulations in which thepharmacologically active base is a hydroxide-releasing agent, it ispreferred although not essential that water be present. Thus, such aformulation may be aqueous, i.e., contain water, or may be nonaqueousand optionally used in combination with an occlusive overlayer so thatmoisture evaporating from the body surface is maintained within theformulation upon application to the body surface and thereafter.

Formulations of the invention may optionally contain a pharmaceuticallyacceptable viscosity enhancer and/or film former. A viscosity enhancerincreases the viscosity of the formulation so as to inhibit its spreadbeyond the site of application. Balsam Fir (Oregon) is an example of apharmaceutically acceptable viscosity enhancer.

A film former, when it dries, forms a protective film over the site ofapplication. The film inhibits removal of the active ingredient andkeeps it in contact with the site being treated. An example of a filmformer that is suitable for use in this invention is Flexible Collodion,USP. As described in Remington: The Science and Practice of Pharmacy,19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), at page 1530,collodions are ethyl ether/ethanol solutions containing pyroxylin (anitrocellulose) that evaporate to leave a film of pyroxylin. A filmformer may act additionally as a carrier. Solutions that dry to form afilm are sometimes referred to as paints.

Ointments, as is well known in the art of pharmaceutical formulation,are semisolid preparations that are typically based on petrolatum orother petroleum derivatives. The specific ointment base to be used, aswill be appreciated by those skilled in the art, is one that willprovide for optimum drug delivery, and, preferably, will provide forother desired characteristics as well, e.g., emolliency or the like. Aswith other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack PublishingCo., 1995), at pages 1399-1404, ointment bases may be grouped in fourclasses: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, see Remington: The Scienceand Practice of Pharmacy for further information.

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier, and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic, or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferred“organic macromolecules,” i.e., gelling agents, are crosslinked acrylicacid polymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methyl cellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof.

Lotions, which are preferred for delivery of cosmetic agents, arepreparations to be applied to the skin surface without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable base. Depending on the nature of the base, pastes aredivided between fatty pastes or those made from a single-phase aqueousgels. The base in a fatty paste is generally petrolatum or hydrophilicpetrolatum or the like. The pastes made from single-phase aqueous gelsgenerally incorporate carboxymethylcellulose or the like as a base.

Plasters are comprised of a pasty mixture that is spread on the body,either directly or after being saturated into a base material such ascloth. Medications, including the bases of the invention, may bedissolved or dispersed within the plaster to make a medicated plaster.

Bioadhesives are preparations that adhere to surfaces of body tissues.Polymeric bioadhesive formulations are well known in the art; see, forexample, Heller et al., “Biodegradable polymers as drug deliverysystems”, in Chasin, M. and Langer, R., eds.: Dekker, New York,pp.121-161 (1990); and U.S. Pat. No. 6,201,065. Suitable non-polymericbioadhesives are also known in the art, including certain fatty acidesters (U.S. Pat. No. 6,228,383).

Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged) and neutralpreparations. Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol(DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

Micelles are known in the art to be comprised of surfactant moleculesarranged so that their polar headgroups form an outer spherical shell,while the hydrophobic, hydrocarbon chains are oriented towards thecenter of the sphere, forming a core. Micelles form in an aqueoussolution containing surfactant at a high enough concentration so thatmicelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyl8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol30. Micelle formulations can be used in conjunction with the presentinvention either by incorporation into the reservoir of a topical ortransdermal delivery system, or into a formulation to be applied to thenail and surrounding tissues.

Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. Microspheres are generally, although not necessarily,formed from synthetic or naturally occurring biocompatible polymers, butmay also be comprised of charged lipids such as phospholipids.Preparation of microspheres is well known in the art and described inthe pertinent texts and literature.

Although the bases herein are particularly effective permeationenhancers, it may be desirable, particularly with weaker bases orthicker nails, to include an added permeation enhancer in theformulation. Examples of suitable enhancers include, but are not limitedto, ethers such as diethylene glycol monoethyl ether (availablecommercially as Transcutol®) and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Pat. No.4,783,450); alcohols such as ethanol, propanol, octanol, benzyl alcohol,and the like; polyethylene glycol and esters thereof such aspolyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No.4,568,343); amides and other nitrogenous compounds such as urea,dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone® and sulfoxides such as DMSO andC₁₀MSO may also be used, but are less preferred.

Most preferred enhancers are those lipophilic co-enhancers typicallyreferred to as “plasticizing” enhancers, i.e., enhancers that have amolecular weight in the range of about 150 to 1000, an aqueoussolubility of less than about 1 wt. %, preferably less than about 0.5wt. %, and most preferably less than about 0.2 wt. %. The Hildebrandsolubility parameter of plasticizing enhancers is in the range of about2.5 to about 10, preferably in the range of about 5 to about 10. Suchenhancers are described in detail in co-pending, commonly assigned U.S.patent application Ser. No. 09/738,410, filed on Dec. 14, 2000, which isnow U.S. Pat. No. 6,586,000, and in International Patent Application No.PCT/US00/34483, filed on Dec. 15, 2000, published Jun. 21, 2001 as WO01/43775 A2. Preferred lipophilic enhancers are fatty esters, fattyalcohols, and fatty ethers. Examples of specific and most preferredfatty acid esters include methyl laurate, ethyl oleate, propylene glycolmonolaurate, propylene glycerol dilaurate, glycerol monolaurate,glycerol monooleate, isopropyl n-decanoate, and octyldodecyl myristate.Fatty alcohols include, for example, stearyl alcohol and oleyl alcohol,while fatty ethers include compounds wherein a diol or triol, preferablya C₂-C₄ alkane diol or triol, are substituted with one or two fattyether substituents.

Additional permeation enhancers will be known to those of ordinary skillin the art of topical drug delivery, and/or are described in thepertinent texts and literature. See, e.g., Percutaneous PenetrationEnhancers, Smith et al., editors (CRC Press, 1995).

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solvents, including relativelysmall amounts of alcohol, may be used to solubilize certain formulationcomponents. The present formulations may also include conventionaladditives such as opacifiers, antioxidants, fragrance, colorants,gelling agents, thickening agents, stabilizers, surfactants, and thelike. Other agents may also be added, such as antimicrobial agents, toprevent spoilage upon storage, i.e., to inhibit growth of microbes suchas bacteria, yeasts, and molds. Suitable antimicrobial agents aretypically selected from the group consisting of the methyl and propylesters of p-hydroxybenzoic acid (i.e., methyl and propyl paraben),sodium benzoate, sorbic acid, imidurea, and combinations thereof.

The formulations may also contain irritation-mitigating additives tominimize or eliminate the possibility of skin irritation or skin damageresulting from the base or other components of the composition. Suitableirritation-mitigating additives include, for example: -tocopherol;monoamine oxidase inhibitors, particularly phenyl alcohols such as2-phenyl-1-ethanol; glycerin; salicylic acids and salicylates; ascorbicacids and ascorbates; ionophores such as monensin; amphiphilic amines;ammonium chloride; N-acetylcysteine; cis-urocanic acid; capsaicin; andchloroquine. The irritant-mitigating additive, if present, may beincorporated into the present formulations at a concentration effectiveto mitigate irritation or skin damage, typically representing not morethan about 20 wt. %, more typically not more than about 5 wt. %, of thecomposition.

The base may also be administered through the nail and surroundingtissues using a conventional skin patch, wherein the agent is containedwithin a laminated structure that serves as a drug delivery device to beaffixed to the body surface. In such a structure, the pharmaceuticalformulation is contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated structure may contain a single reservoir,or it may contain multiple reservoirs.

In one embodiment, the reservoir comprises a polymeric matrix of apharmaceutically acceptable adhesive material that serves to affix thesystem to the nail or skin during drug delivery; typically, the adhesivematerial is a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin or nail contact, and that should be physically andchemically compatible with the base and any carriers, vehicles or otheradditives that are present. Examples of suitable adhesive materialsinclude, but are not limited to, the following: polyethylenes;polysiloxanes; polyisobutylenes; polyacrylates; polyacrylamides;polyurethanes; plasticized ethylene-vinyl acetate copolymers; and tackyrubbers such as polyisobutene, polybutadiene, polystyrene-isoprenecopolymers, polystyrene-butadiene copolymers, and neoprene(polychloroprene). Preferred adhesives are polyisobutylenes.

The backing layer functions as the primary structural element of thetransdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing drug, base, or components of theformulation contained within the device. The backing is preferablycomprised of a flexible elastomeric material that serves as a protectivecovering to prevent loss of drug and/or vehicle via transmission throughthe upper surface of the patch, and will preferably impart a degree ofocclusivity to the system, such that the area of the body surfacecovered by the patch becomes hydrated during use. The material used forthe backing layer should permit the device to follow the contours of theskin and nail and be worn comfortably on areas of skin such as at jointsor other points of flexure, that are normally subjected to mechanicalstrain, with little or no likelihood of the device disengaging from theskin due to differences in the flexibility or resiliency of the skin andthe device. The materials used as the backing layer are either occlusiveor permeable, as noted above, although occlusive backings are preferred,and are generally derived from synthetic polymers (e.g., polyester,polyethylene, polypropylene, polyurethane, polyvinylidine chloride, andpolyether amide), natural polymers (e.g., cellulosic materials), ormacroporous woven and nonwoven materials.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice so that the system may be affixed to the nail and/or skinsurrounding the nail. The release liner should be made from adrug/vehicle impermeable material, and is a disposable element thatserves only to protect the device prior to application. Typically, therelease liner is formed from a material impermeable to thepharmacologically active agent and the base, and which is easilystripped from the patch prior to use.

In an alternative embodiment, the active agent-containing reservoir andskin or nail contact adhesive are present as separate and distinctlayers, with the adhesive underlying the reservoir. In such a case, thereservoir may be a polymeric matrix as described above. Alternatively,the reservoir may be comprised of a liquid or semisolid formulationcontained in a closed compartment or “pouch,” or it may be a hydrogelreservoir, or may take some other form. Hydrogel reservoirs areparticularly preferred herein. As will be appreciated by those skilledin the art, hydrogels are macromolecular networks that absorb water andthus swell but do not dissolve in water. That is, hydrogels containhydrophilic functional groups that provide for water absorption, but thehydrogels are comprised of crosslinked polymers that give rise toaqueous insolubility. Generally, then, hydrogels are comprised ofcrosslinked hydrophilic polymers such as a polyurethane, a polyvinylalcohol, a polyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone,a poly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer ormixture thereof. Particularly preferred hydrophilic polymers arecopolymers of HEMA and polyvinylpyrrolidone.

Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe an active agent, an enhancer, or some other component contained inthe drug delivery system. A rate-controlling membrane, if present, willbe included in the system on the skin side of one or more of the drugreservoirs. The materials used to form such a membrane are selected tolimit the flux of one or more components contained in the drugformulation. Representative materials useful for formingrate-controlling membranes include polyolefins such as polyethylene andpolypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer,ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetatecopolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinylpropylacetate copolymer, polyisoprene, polyacrylonitrile,ethylene-propylene copolymer, and the like.

Generally, the underlying surface of the transdermal device, i.e., thenail and skin contact area, has an area in the range of about 0.25 cm²to 12 cm², preferably about 0.5 cm² to 7 cm², more preferably about 1cm² to 5 cm². That area will vary, of course, with the size of the areato be treated. Larger patches will be necessary to accommodate largernails, whereas smaller patches can be used for smaller nails.

Such drug delivery systems may be fabricated using conventional coatingand laminating techniques known in the art. For example, adhesive matrixsystems can be prepared by casting a fluid admixture of adhesive, activeagent and vehicle onto the backing layer, followed by lamination of therelease liner. Similarly, the adhesive mixture may be cast onto therelease liner, followed by lamination of the backing layer.Alternatively, the drug reservoir may be prepared in the absence of drugor excipient, and then loaded by “soaking” in a drug/vehicle mixture. Ingeneral, these patches are fabricated by solvent evaporation, filmcasting, melt extrusion, thin film lamination, die cutting, or the like.The active agent will generally be incorporated into the device duringpatch manufacture rather than subsequent to preparation of the device.

In a preferred delivery system, an adhesive overlayer that also servesas a backing for the delivery system is used to better secure the patchto the nail and surrounding tissue. This overlayer is sized such that itextends beyond the drug reservoir so that adhesive on the overlayercomes into contact with the body surface. In many cases, the overlayerwill make contact with the skin surrounding the nail, while the drugreservoir is positioned over the nail, particularly the infectedportions of the nail. The overlayer is useful because the adhesive/drugreservoir layer may lose its adhesion a few hours after application dueto hydration. By incorporating such adhesive overlayer, the deliverysystem remains in place for the required period of time.

Other types and configurations of topically applied drug deliverysystems may also be used in conjunction with the present invention, aswill be appreciated by those skilled in the art of topical drugdelivery. See, for example, Ghosh, Transdermal and Topical Drug DeliverySystems (Interpharm Press, 1997), particularly Chapters 2 and 8.

V. Administration

The method of delivery may vary, but necessarily involves application ofa formulation of the invention to an area of body surface affected withonychomycosis. A cream, ointment, paste, plaster, or lotion may bespread on the affected area and gently rubbed in. Similarly, a polymericor other bioadhesive formulation may be spread or dabbed on the affectedarea. A solution may be applied in the same ways, but more typicallywill be applied with a dropper, swab, or the like, and carefully appliedto the affected area. Petrolatum may be spread on the skin surroundingthe affected area to protect it from possible irritation duringtreatment.

The dose regimen will depend on a number of factors that may readily bedetermined, such as the areal extent and thickness of the affected nailand the responsiveness of the infection to treatment, but will normallybe one or more doses per day, with a course of treatment lasting fromseveral weeks to several months, or until a cure is effected or asignificant reduction of the infection is achieved. One of ordinaryskill may readily determine optimum dosages, dosing methodologies andrepetition rates. In general, it is contemplated that the formulationwill be applied one to four times daily. With a skin patch, the deviceis generally maintained in place on the body surface throughout a drugdelivery period, typically in the range of 8 to 72 hours, and replacedas necessary.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description is intended to illustrate and not limit the scopeof the invention. Other aspects, advantages, and modifications will beapparent to those skilled in the art to which the invention pertains.Furthermore, the practice of the present invention will employ, unlessotherwise indicated, conventional techniques of drug formulation,particularly topical and transdermal drug formulation, which are withinthe skill of the art. Such techniques are fully explained in theliterature. See Remington: The Science and Practice of Pharmacy, citedsupra, as well as Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 9th Ed. (New York: McGraw-Hill, 1996).

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties.

Experimental

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of pharmaceutical formulation and thelike, which are within the skill of the art. Such techniques are fullyexplained in the literature. In the following examples, efforts havebeen made to ensure accuracy with respect to numbers used (e.g.,amounts, temperatures, etc.) but some experimental error and deviationshould be accounted for. Unless otherwise indicated, temperature is indegrees Celsius and pressure is at or near atmospheric pressure at sealevel. All reagents were obtained commercially unless otherwiseindicated.

EXAMPLE 1

A topical gel of the invention is prepared by conventionalpharmaceutical methods. The indicated amounts of the followingingredients are used:

Ingredient Amount Purified water 600 grams Polyethylene glycol 400 gramsPotassium hydroxide 0.01 gram Edetate disodium 0.1 gram Carbomer 934P12.5 grams Poloxamer 407 2.0 grams Polysorbate 40 2.0 grams Butylatedhydroxytoluene 0.5 grams Benzyl alcohol 10.0 grams

The carbomer 934P and the edetate disodium are added to 250 mL of thepurified water, and the mixture is homogenized at low speed until thecarbomer is dispersed. Next, the polaxamer 407, mixed with 250 mL of thepurified water, is added to the carbomer mixture, and the resultingmixture is homogenized at low speed. The potassium hydroxide, dissolvedin 100 mL of purified water, is added to this mixture, and the resultingmixture (Mixture 1) is homogenized at low speed. In a separatecontainer, the polysorbate 40 and the butylated hydroxytoluene are addedto the polyethylene glycol, and the resulting mixture is heated to 65°C. and maintained at this temperature until all the compounds aredissolved; this mixture is then allowed to cool to room temperature, atwhich time the benzyl alcohol is added, and the resulting mixture ishomogenized at low speed. This mixture is then added to Mixture 1, andthe resulting mixture is mixed at low speed until it is homogeneous,forming a gel of the invention.

EXAMPLE 2

A topical cream of the invention is prepared by conventionalpharmaceutical methods. The indicated amounts of the followingingredients are used:

Ingredient Amount Purified water 370 grams White petrolatum 250 gramsStearyl alcohol 250 grams Propylene glycol 120 grams Sodium laurylsulfate 10 grams Methylparaben 0.25 gram Propylparaben 0.15 gramPotassium hydroxide 0.01 gram

The stearyl alcohol and the white petrolatum are melted together on asteam bath, and then maintained at a temperature of approximately 75° C.The other ingredients are then added, after previously having beendissolved in the purified water and warmed to 75° C., and the resultingmixture is stirred until it congeals into a cream of the invention.

EXAMPLE 3

A skin patch of the invention is prepared by conventional pharmaceuticalmethods. A square piece of sterile, finely woven gauze one centimeter oneach side is placed in the center of a square piece of occlusivesurgical adhesive tape two centimeters on each side. To the gauze isapplied 0.4 mL of the gel of Example 1; the gel is allowed to soak intothe gauze. This skin patch of the invention is used within three hoursof preparation.

EXAMPLE 4

The gel formulation of Example 1 is provided to patients having distalsubungual onychomycosis. Each infected nail to be treated is examined,cultured, and photographed before treatment begins. Culturing isperformed as described by B. Elewski (Journal of the American Academy ofDermatology, v. 35 (number 3, part 2): S6-S9): The nail to be sampled isfirst swabbed liberally with alcohol to eliminate as many bacteria aspossible, as bacteria could overgrow and inhibit the growth of fungi. Asmall curette or special nail clipper is used to cut away the distal endof the nail plate; a curette is then used to scrape debris from the nailbed at a site as close to the cuticle as possible; scrapings from theunder surface of the nail plate may be included. The shavings specimenis divided in half, each half being spread on a petri dish containingSabouraud glucose agar. One petri dish is cycloheximide-free, while theother contains cycloheximide in the agar. Chloramphenicol is usuallyadded to the culture media in both dishes to inhibit bacterial growth.The dishes are incubated for 7 to 14 days and then examinedmicroscopically to identify any fungal or yeast growth. As cycloheximideinhibits nondermatophyte growth but not dermatophyte growth, coloniesthat appear on both dishes are likely to be dermatophytes, while thosethat only appear on the cycloheximide-free dish are likely to benondermatophyte species.

Each of the patients is instructed to topically apply the formulation ofthe invention to the affected nail or nails twice daily for eight weeks.The patients return to the clinic every seven days, when each nail isagain examined, cultured, and photographed. It is found that most of theinfected nails are significantly improved in clinical appearance andthat the degree of mycological infection as revealed by culturing issignificantly reduced after three weeks and that most infections haveentirely resolved after eight weeks of treatment.

EXAMPLE 5

The skin patches of Example 3 are provided to patients havingonychomycosis on one or more fingernails. Each infected nail to betreated is examined, cultured, and photographed before treatment begins.Culturing is performed as in Example 4. Each of the patients isinstructed to topically apply a skin patch of the invention to theaffected nail or nails, replacing the old patch with a new one every 48hours. The patients return to the clinic every seven days, when eachnail is again examined, cultured, and photographed. It is found thatmost of the infected nails are significantly improved in clinicalappearance and that the degree of mycological infection as revealed byculturing is significantly reduced after three weeks and that mostinfections have entirely resolved after eight weeks of treatment.

EXAMPLE 6

The cream formulation of Example 2 is provided to patients having whitesuperficial onychomycosis. Each infected nail to be treated is examined,cultured, and photographed before treatment begins. Culturing isperformed as in Example 4, except that the specimen is obtained byscraping debris from the surface of the infected nail with a No. 15blade scalpel or a sharp curette. Each of the patients is instructed totopically apply the formulation of the invention to the affected nail ornails twice daily for eight weeks. The patients return to the clinicevery seven days, when each nail is again examined, cultured, andphotographed. It is found that most of the infected nails aresignificantly improved in clinical appearance and that the degree ofmycological infection as revealed by culturing is significantly reducedafter three weeks and that most infections have entirely resolved aftereight weeks of treatment.

1. A method of treating an individual afflicted with onychomycosis,comprising topically applying to an affected area of the individual'snail and surrounding tissue a formulation consisting essentially of apharmaceutically acceptable topical carrier, an effectiveskin-permeation enhancing amount of an inorganic hydroxide or a mixturethereof, and a therapeutically effective amount of an antifungal agent,wherein the effective skin-permeation enhancing amount corresponds to aconcentration sufficient to provide a formulation pH in the range ofapproximately 7.5 to 13.0, wherein the formulation does not contain anyadditional permeation enhancers.
 2. The method of claim 1, wherein theantifungal agent is selected from the group consisting of terbinatine,amorolfine, ciclopirox olamine, flucytosine, griseofulvin, haloprogrin,potassium iodide, sodium pyrithione, undecylenic acid, imidazoles,triazoles, allylamines, polyene antifungal antibiotics, antifungalorganic acids, and a propylene glycol-urea-lactic acid combination. 3.The method of claim 2, wherein the antifungal agent is selected from thegroup consisting of amorolfine, ciclopirox olamine, flucytosine,griseofulvin, haloprogrin, potassium iodide, sodium pyrithione,undecylenic acid, bifonazole, butoconazole, clotrimazole, econazole,ketoconazole, miconazole, oxiconazole, sulconazole, itraconazole,fluconazole, terconazole, naftifine, amphotericin B, nystatin, benzoicacid, salicylic acid, propionic acid, and caprylic acid.
 4. The methodof claim 2, wherein the pharmacologically active antifungal agent isciclopirox olamine.
 5. The method of claim 2, wherein thepharmacologically active antifungal agent is terbinafine.
 6. The methodof claim 2, wherein the pharmacologically active antifungal agent isitraconazole.
 7. The method of claim 2, wherein the pharmacologicallyactive antifungal agent is fluconazole.
 8. The method of claim 2,wherein the pharmacologically active antifungal agent is clotrimazole.9. The method of claim 2, wherein the pharmacologically activeantifungal agent is nystatin.
 10. The method of claim 1, wherein the pHis in the range of approximately 8.0 to 11.5.
 11. The method of claim 1,wherein the pH is in the range of approximately 8.5 to 10.5.
 12. Themethod of claim 1, wherein the formulation is aqueous.
 13. The method ofclaim 12, wherein the aqueous formulation is selected from the groupconsisting of a cream, a gel, a lotion, a paste, and a solution.
 14. Themethod of claim 13, wherein the aqueous formulation is a cream.
 15. Themethod of claim 13, wherein the aqueous formulation is a gel.
 16. Themethod of claim 13, wherein the aqueous formulation is a lotion.
 17. Themethod of claim 13, wherein the aqueous formulation is a solution. 18.The method of claim 13, wherein the aqueous formulation is a paste. 19.The method of claim 1, wherein the formulation is a bioadhesive.
 20. Themethod of claim 1, wherein the formulation is in a medicated plaster.21. The method of claim 1, wherein the formulation is in a skin patch.22. The method of claim 1, wherein the inorganic hydroxide is selectedfrom the group consisting of ammonium hydroxide, alkali metalhydroxides, alkaline earth metal hydroxides, and mixtures thereof. 23.The method of claim 22, wherein the inorganic hydroxide is selected fromthe group consisting of ammonium hydroxide, sodium hydroxide, calciumhydroxide, potassium hydroxide, magnesium hydroxide, and mixturesthereof.
 24. The method of claim 23, wherein the inorganic hydroxide issodium hydroxide.
 25. The method of claim 1, wherein the formulationcontains an additional active antifungal agent.
 26. The method of claim1, wherein the formulation is applied periodically over an extended timeperiod.
 27. The method of claim 1, wherein the formulation is appliedapproximately twice weekly.
 28. The method of claim 1, wherein theformulation is applied once daily.
 29. The method of claim 1, whereinthe formulation is applied twice daily.
 30. The method of claim 1,wherein the formulation is applied on an as-needed basis.
 31. The methodof claim 26, wherein said extended time period is at least three months.32. The method of claim 31, wherein said extended time period is atleast four months.